Obesity is a complex disorder resulting from misregulation of specific biological pathways controlling the balance between energy consumption and expenditure, and is associated with health problems ranging from heart disease and diabetes to several kinds of cancer. Conversely, caloric restriction has been shown to result in a reduction of incidence of spontaneous tumors in laboratory mice. However, it is clear that obesity is not simply an effect of excessive food intake. Significant progress has been made towards identifying pathways involved in obesity, but a deeper understanding of the disease is required in order to meet the growing demand for effective treatments. The field of obesity research is in need of an experimental system that can combine amenability to genetic manipulation with some of the physiological complexity of humans. The proposed research will develop Drosophila melanogaster as a model system to identify new pathways controlling energy homeostasis. Flies offer extensive genetic tools and the physiological complexity required for these studies, as they possess sensory, circulatory and storage organs. Maintaining energy balance requires coordination of the nervous system (sensing satiety and regulating behavior) and energy storage tissues (storing energy as fat/sugar or mobilizing it). The proposed studies will determine the effects of modified diets on the types and levels of energy storage, and identify pathways comprising the regulatory network for energy homeostasis, including which organs sense and process food sources and physiological changes in energy levels. Specifically, these experiments aim to: (1) determine the effects of diet on the balance between intake (amount/type of food consumed) and usage (amount/type of energy stored);(2) address the role of the nervous system in regulating overall physiological energy balance and identify which specific regions of the brain are involved;and (3) identify inter-organ communication pathways responsible for maintaining the organism energy balance. Developing fruit flies will be fed modified diets and effects on levels of fat and other forms of energy storage, rates of food consumption, and overall growth and development will be assessed. To identify regions of the brain required for normal energy balance, genetically engineered flies will be used to ablate the function of specific groups of neurons and determine the effects on levels of fat stored and food ingested. Finally, a genome-wide screen will be performed to identify genes modifying fat storage and/or rates of food consumption. Knowledge of the diets and physiological conditions prone to inducing obesity will improve our understanding of this disorder and identify potential targets for both its treatment and prevention.